Lymphoma and Myeloma Cell Resistance to Cytotoxic Agents and Ionizing Radiations Is Not Affected by Exposure to Anti–IL-6 Antibody

Background: Production of high levels of IL-6 is often correlated with resistance to cytotoxics or ionizing radiations, in cancer cell lines as in various cancer patients. We investigated whether monoclonal antibodies directed against IL-6 may enable to reverse resistance of cancer cell lines. Methodology/Principal Findings: We exposed ten haematological cancer cells from lymphoma, myeloma, or leukemia origins to cytotoxics or ionizing radiations and assessed the effects of anti–IL-6 antibody addition on cell proliferation, apoptosis, or IL-6 signaling. A strong correlation between IL-6 secretion, measured by ELISA, and resistance to doxorubicin as ionizing radiations was observed in the multiple myeloma U266 and the Burkitt’s lymphoma Daudi and Namalwa cells. Although an anti–IL-6 antibody combined to both treatments efficiently blocked IL-6 signaling in U266 cells, expressing the IL-6 receptor gp80, it did not increase treatment-induced anti-proliferative and pro-apoptotic effects on these cells, as well as on Daudi and Namalwa cells. This lack of effect could be related to diverse factors: 1) a higher release of the soluble form of IL-6 receptor gp80 in response to doxorubicin and irradiation from all cell lines, 2) an impaired level of the IL-6 pathway inhibitor SOCS3 in Daudi cells, and 3) an increased release of IL-10 and TNFa, two cytokines involved in cell radio- and chemoresistance. Conclusions/Significance: These data support the fact that IL-6 is not the preponderant actor of cell resistance to cytotoxic

miRNA Profiling: How to Bypass the Current Difficulties in the Diagnosis and Treatment of Sarcomas

Sarcomas are divided into a group with specific alterations and a second presenting a complex karyotype, sometimes difficult to diagnose or with few therapeutic options available. We assessed if miRNA profiling by TaqMan low density arrays could predict the response of undifferentiated rhabdomyosarcoma (RMS) and osteosarcoma to treatment. We showed that miRNA signatures in response to a therapeutic agent (chemotherapy or the mTOR inhibitor RAD-001) were cell and drug specific on cell lines and a rat osteosarcoma model. This miRNA signature was related to cell or tumour sensitivity to this treatment and might be not due to chromosomal aberrations, as revealed by a CGH array analysis of rat tumours. Strikingly, miRNA profiling gave promising results for patient rhabdomyosarcoma, discriminating all types of RMS: (Pax+) or undifferentiated alveolar RMS as well as embryonal RMS. As highlighted by these results, miRNA profiling emerges as a potent molecular diagnostic tool for complex karyotype sarcomas

Exosomal microRNAs as a potential therapeutic strategy in hepatocellular carcinoma

International audienc

Epigenetic modulation of immunity: towards new therapeutic avenues in hepatocellular carcinoma?

International audienc

Epigenetic mechanisms of liver tumor resistance to immunotherapy

International audienceHepatocellular carcinoma (HCC) is the most common primary liver tumor, which stands fourth in rank of cancer-related deaths worldwide. The incidence of HCC is constantly increasing in correlation with the epidemic in diabetes and obesity, arguing for an urgent need for new treatments for this lethal cancer refractory to conventional treatments. HCC is the paradigm of inflammation-associated cancer, since more than 80% of HCC emerge consecutively to cirrhosis associated with a vast remodeling of liver microenvironment. In the recent decade, immunomodulatory drugs have been developed and have given impressive results in melanoma and later in several other cancers. In the present review, we will discuss the recent advancements concerning the use of immunotherapies in HCC, in particular those targeting immune checkpoints, used alone or in combination with other anti-cancers agents. We will address why these drugs demonstrate unsatisfactory results in a high proportion of liver cancers and the mechanisms of resistance developed by HCC to evade immune response with a focus on the epigenetic-related mechanisms

Early HCC treatment: a future strategy against interferon/miR-484 axis to revert precancerous lesions?

International audienceNo abstract availabl

Les microARN dans le cancer du foie : à l'orée de nouvelles thérapies ciblées ?

International audienceLes microARN (miARN) sont de petits ARN non-codants contrôlant négativement l'expression de leurs cibles. Par leur mutiplicité d'action, ils jouent un rôle majeur dans nombre de processi physiologiques et dans la tumorigenèse. L'identification de signatures miARN pour une grande variété de tumeurs, dont les carcinomes hépatocellulaires (CHC), ont mis en évidence le rôle ambivalent des miARN, à la fois oncogène et suppresseur de tumeurs. Dans cette revue, nous faisons un tour d'horizon des connaissances actuelles au sujet de la dérégulation des miARN dans les maladies du foie. Toutes les études dédiées aux miARN sont en faveur de leur utilisation en tant qu'outil diagnostique, pronostique et thérapeutique. Un intérêt tout particulier sera porté aux stratégies thérapeutiques qui ciblent les miARN dans le CHC

Noncoding RNAs in liver cancer patients

International audienc

Les microARN dans le cancer du foie

Les microARN (miARN) sont de petits ARN non codants qui contrôlent négativement l’expression de leurs cibles. Par leur mutiplicité d’action, ils jouent un rôle majeur dans nombre de processus physiologiques et dans la tumorigenèse. L’identification de signatures miARN pour une grande variété de tumeurs, dont les carcinomes hépatocellulaires (CHC), a mis en évidence le rôle ambivalent des miARN, à la fois oncogènes et suppresseurs de tumeurs. Dans cette revue, nous faisons un tour d’horizon des connaissances actuelles de la dérégulation des miARN dans les maladies du foie. Toutes les études dédiées aux miARN sont en faveur de leur utilisation en tant qu’outil diagnostique, pronostique et thérapeutique. Un intérêt tout particulier sera porté aux stratégies thérapeutiques qui ciblent les miARN dans le CHC